MicroRNA history : discovery, recent applications and next frontiers

We thank the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for English language editing of the manuscript.Since 1993, when the first small non-coding RNA was identified, our knowledge about microRNAs has grown exponentially. In this review, we focus on the main progress in this field and discuss the most important findings under a historical perspective. In addition, we examine microRNAs as markers ofdisease diagnosis and prognosis, and as new therapeutic targets.M.I.A is supported by a PhD fellowship (SFRH/BD/47031/2008) from FCT (Fundação para a Ciência e Tecnologia) from Portugal. G.A.C. is supported as a Fellow at The University of Texas MD Anderson Research Trust, as a Fellow of The University of Texas System Regents Research Scholar, and by the CLL Global Research Foundation. Work in Dr. Calin’s laboratory was supported in part by NIH, by DoD, by 2009 Seena Magowitz – Pancreatic Cancer Action Network – AACR Pilot Grant and by the U.S./European Alliance for the Therapy of CLL

MicroRNA-383 located in frequently deleted chromosomal locus 8p22 regulates CD44 in prostate cancer.

A major genomic alteration in prostate cancer (PCa) is frequent loss of chromosome (chr) 8p with a common region of loss of heterozygosity (LOH) at chr8p22 locus. Genomic studies implicate this locus in the initiation of clinically significant PCa and with progression to metastatic disease. However, the genes within this region have not been fully characterized to date. Here we demonstrate for the first time that a microRNA component of this region-miR-383-is frequently downregulated in prostate cancer, has a critical role in determining tumor-initiating potential and is involved in prostate cancer metastasis via direct regulation of CD44, a ubiquitous marker of PCa tumor-initiating cells (TICs)/stem cells. Expression analyses of miR-383 in PCa clinical tissues established that low miR-383 expression is associated with poor prognosis. Functional data suggest that miR-383 regulates PCa tumor-initiating/stem-like cells via CD44 regulation. Ectopic expression of miR-383 inhibited tumor-initiating capacity of CD44+ PCa cells. Also, 'anti-metastatic' effects of ectopic miR-383 expression were observed in a PCa experimental metastasis model. In view of our results, we propose that frequent loss of miR-383 at chr8p22 region leads to tumor initiation and prostate cancer metastasis. Thus, we have identified a novel finding that associates a long observed genomic alteration to PCa stemness and metastasis. Our data suggest that restoration of miR-383 expression may be an effective therapeutic modality against PCa. Importantly, we identified miR-383 as a novel PCa tissue diagnostic biomarker with a potential that outperforms that of serum PSA

Lagrangian Variational Framework for Boundary Value Problems

A boundary value problem is commonly associated with constraints imposed on a system at its boundary. We advance here an alternative point of view treating the system as interacting "boundary" and "interior" subsystems. This view is implemented through a Lagrangian framework that allows to account for (i) a variety of forces including dissipative acting at the boundary; (ii) a multitude of features of interactions between the boundary and the interior fields when the boundary fields may differ from the boundary limit of the interior fields; (iii) detailed pictures of the energy distribution and its flow; (iv) linear and nonlinear effects. We provide a number of elucidating examples of the structured boundary and its interactions with the system interior. We also show that the proposed approach covers the well known boundary value problems.Comment: 41 pages, 3 figure

Exact N=2 Supergravity Solutions With Polarized Branes

We construct several classes of exact supersymmetric supergravity solutions describing D4 branes polarized into NS5 branes and F-strings polarized into D2 branes. These setups belong to the same universality class as the perturbative solutions used by Polchinski and Strassler to describe the string dual of N=1* theories. The D4-NS5 setup can be interpreted as a string dual to a confining 4+1 dimensional theory with 8 supercharges, whose properties we discuss. By T-duality, our solutions give Type IIB supersymmetric backgrounds with polarized branes.Comment: 22 pages. v2 - references added, details clarifie

Holomorphic matrix models

This is a study of holomorphic matrix models, the matrix models which underlie the conjecture of Dijkgraaf and Vafa. I first give a systematic description of the holomorphic one-matrix model. After discussing its convergence sectors, I show that certain puzzles related to its perturbative expansion admit a simple resolution in the holomorphic set-up. Constructing a `complex' microcanonical ensemble, I check that the basic requirements of the conjecture (in particular, the special geometry relations involving chemical potentials) hold in the absence of the hermicity constraint. I also show that planar solutions of the holomorphic model probe the entire moduli space of the associated algebraic curve. Finally, I give a brief discussion of holomorphic $ADE$ models, focusing on the example of the $A_2$ quiver, for which I extract explicitly the relevant Riemann surface. In this case, use of the holomorphic model is crucial, since the Hermitian approach and its attending regularization would lead to a singular algebraic curve, thus contradicting the requirements of the conjecture. In particular, I show how an appropriate regularization of the holomorphic $A_2$ model produces the desired smooth Riemann surface in the limit when the regulator is removed, and that this limit can be described as a statistical ensemble of `reduced' holomorphic models.Comment: 45 pages, reference adde

Measurement of 21 cm brightness fluctuations at z ~ 0.8 in cross-correlation

In this letter, 21 cm intensity maps acquired at the Green Bank Telescope are cross-correlated with large-scale structure traced by galaxies in the WiggleZ Dark Energy Survey. The data span the redshift range 0.6 < z < 1 over two fields totaling ~41 deg. sq. and 190 hours of radio integration time. The cross-correlation constrains Omega_HI b_HI r = [0.43 \pm 0.07 (stat.) \pm 0.04(sys.)] x 10^-3, where Omega_HI is the neutral hydrogen HI fraction, r is the galaxy-hydrogen correlation coefficient, and b_HI is the HI bias parameter. This is the most precise constraint on neutral hydrogen density fluctuations in a challenging redshift range. Our measurement improves the previous 21 cm cross-correlation at z ~ 0.8 both in its precision and in the range of scales probed.Comment: 5 pages, 2 figures. As published in Ap

A novel gamma-N-methylaminobutyrate demethylating oxidase involved in catabolism of the tobacco alkaloid nicotine by Arthrobacter nicotinovorans pAO1

Nicotine catabolism, linked in Arthrobacter nicotinovorans to the presence of the megaplasmid pAO1, leads to the formation of gamma-N-methylaminobutyrate from the pyrrolidine ring of the alkaloid. Until now the metabolic fate of gamma-N-methylaminobutyrate has been unknown. pAO1 carries a cluster of ORFs with similarity to sarcosine and dimethylglycine dehydrogenases and oxidases, to the bifunctional enzyme methylenetetrahydrofolate dehydrogenase/cyclohydrolase and to formyltetrahydrofolate deformylase. We cloned and expressed the gene carrying the sarcosine dehydrogenase-like ORF and showed, by enzyme activity, spectrophotometric methods and identification of the reaction product as gamma-aminobutyrate, that the predicted 89 395 Da flavoprotein is a demethylating gamma-N-methylaminobutyrate oxidase. Site-directed mutagenesis identified His67 as the site of covalent attachment of FAD and confirmed Trp66 as essential for FAD binding, for enzyme activity and for the spectral properties of the wild-type enzyme. A K-m of 140 mum and a k(cat) of 800 s(-1) was determined when gamma-N-methylaminobutyrate was used as the substrate. Sarcosine was also turned over by the enzyme, but at a rate 200-fold slower than gamma-N-methylaminobutyrate. This novel enzyme activity revealed that the first step in channelling the gamma-N-methylaminobutyrate generated from nicotine into the cell metabolism proceeds by its oxidative demethylation

Chiral field theories from conifolds

We discuss the geometric engineering and large n transition for an N=1 U(n) chiral gauge theory with one adjoint, one conjugate symmetric, one antisymmetric and eight fundamental chiral multiplets. Our IIB realization involves an orientifold of a non-compact Calabi-Yau A_2 fibration, together with D5-branes wrapping the exceptional curves of its resolution as well as the orientifold fixed locus. We give a detailed discussion of this background and of its relation to the Hanany-Witten realization of the same theory. In particular, we argue that the T-duality relating the two constructions maps the Z_2 orientifold of the Hanany-Witten realization into a Z_4 orientifold in type IIB. We also discuss the related engineering of theories with SO/Sp gauge groups and symmetric or antisymmetric matter.Comment: 34 pages, 8 figures, v2: References added, minor correction